Science —

The origin of life: putting chemistry inside a cell

Jack Szostak has decided to drop the work that won him a Nobel Prize, and …

The fact that RNA appears to play a role in the chemical reactions that take place at a ribosome was one of the pieces of evidence that helped point to our current model for the origin of life: the RNA world, in which RNA both carried genetic information and catalyzed basic metabolic reactions. Nobel Prize winning researcher Jack Szostak's background in RNA chemistry led him to questions about the next step: how did RNA find its way into something that we might recognize as a cell, with membranes surrounding a distinct chemical environment.

At the Lindau meeting, Ars attended a talk by Szostak, who got his Nobel for his work on the RNA involved in telomerase. Szostak announced up front that he hasn't done work in that area for over 20 years, so he wouldn't be talking about it. Instead, he started his talk by describing a number of discoveries that he feels have reenergized origin-of-life research in recent years. The first of these is the discovery of extremophiles—bacteria and archaea living at high temperatures, like acidic or salt-rich environments—which indicates that there's a huge range of interesting chemistry that might be compatible with life. The second has been the discovery of a growing number of exoplanets—Szostak talked easily about things like the latest Kepler results and casually dropped terms like "nulling interferometer" when discussing observatory hardware. These exoplanets, along with discoveries on Saturn's moon Titan, suggested that there would be plenty of potentially interesting chemistry going on in the Universe.

In Szostak's view, interesting chemistry is easy. He also said that Darwinian evolution also makes things easy, since it's possible to take what you've got and radically improve it. So what's bugging him these days is the transition in between the two. How do you move from interesting chemistry to something that can evolve? He's doing this by trying to engineer a system that can make the transition.

His talk focused on several projects that revolved around a single theme: the sorts of molecules we see in current cells are relatively robust and aren't that chemically active, since that limits damage to cells. But these molecules have relatives that are much more reactive, and these compounds might have been involved with some of the early steps in life's origin.

For example, current cells use chemicals called phospholipids to form their membranes. These membranes are robust and help isolate the cell's contents from its environment. But close relatives called fatty acids—lipids without the phosphorous—form looser membranes that allow more extensive exchange with the environment, something that would have been essential for any life that doesn't have a large collection of pores and exchangers in its membranes. So, one of Szostak's students set up a solution of small fatty acid sacs, and started feeding them more of the lipids to see what happened.

Everyone apparently expected that the sacs would simply grow bigger. Instead, they stretched out into long, thin, branched structures. A bit of gentle agitation, and the strands would fragment back into small sacs, starting the cycle all over again. It was a bit like cell division, but without cells, driven purely by physics and chemistry. "It could have been done many years ago, if we knew what to look for," Szostak said.

His team is also looking at the origins of genetic material. Again, things like the nucleotides that make up RNA don't readily engage in chemical reactions—evolution probably selected them because they're relatively stable—so he's focusing on related molecules that are more likely to engage in interesting chemistry. For his lab's current work, this involves a standard-looking DNA or RNA nucleotide (an individual base) with two key differences. On the sugar part of the base, two of the oxygens have been removed, with one of them replaced by an amino group. A ring of nitrogen and carbon atoms is also linked directly to a phosphate.

That makes the chemicals much more reactive. Given a supply of these nucleotides and a template RNA strand, it takes less than a day for 15 bases to be copied, all without any additional chemicals or enzymes. The other interesting thing about this system is that the ringed structure masks some of the phosphate's charge, allowing it to slip across a lipid membrane. You can place template RNA inside lipid sacs and add these chemicals to the outside solution, and the same copying reaction will take place, with only a slight time lag.

Szostak's group is now trying out next-generation versions of these modified nucleotides. All of them make significant changes to the sugar, and hopefully some of them will prove a bit more reactive.

How do you get from there to a system that can evolve? Szostak's lab has found that, if you spike a mix of lipid sacs with a bit of phospholipids (the ones that are in modern membranes), a different dynamic emerges: those sacs that have a bit of phospholipid start eating their neighbors. The more they have, the faster they eat.

This, Szostak said, creates competition and a selective pressure for the ability to grab or make phospholipids, and put more into a membrane. That, in turn, adds another selective pressure: as the cells become less permeable, they need to find a way to shuttle essential molecules to shuffle across the membrane. At this point, the evolution of complexity should be off and running.

Szostak's lab website has excellent videos of some of these projects, and you can see a video of a longer talk on the topic.

Ars Science Video >

Apollo: The Greatest Leap

In honor of the 50th anniversary of the beginning of the Apollo Program, Ars Technica brings you an in depth look at the Apollo missions through the eyes of the participants.

Apollo: The Greatest Leap

Apollo: The Greatest Leap

In honor of the 50th anniversary of the beginning of the Apollo Program, Ars Technica brings you an in depth look at the Apollo missions through the eyes of the participants.

23 Reader Comments

This guy spoke at UMass recently. It was very interesting, but I was looking more for a general 'what are the basic conditions and processes needed for life to start' type talk than a 'look at these cool proof-of-principle projects that demonstrate how life might have gotten started.' The only problem I have with the latter is that it's going to be hard if not impossible to prove that these sorts of processes are what actually happened; they could just be one possible way in which it happened.

There's also a very long ways to go. For example, perhaps other groups are working on it, but Szostak didn't get into how peptide synthesis might have happened in pre-biotic environments.

There's also a very long ways to go. For example, perhaps other groups are working on it, but Szostak didn't get into how peptide synthesis might have happened in pre-biotic environments.

Hey, going from lightning in a bottle to this is a pretty good step.

This is a key point. RNA is pretty unstable stuff compared to DNA (the extra hydroxyl increases susceptibility to base-catalysed hydrolysis). The mind boggles at how tRNA evolved in the prebiotic soup, never mind how this was coupled with the development of the DNA/RNA triplet code.

Not that RNA in itself isn't amazing stuff. Self-splicing RNA (RNA acting as an enzyme, i.e. ribozymes) is edging into Dr Who territory.

There's also a very long ways to go. For example, perhaps other groups are working on it, but Szostak didn't get into how peptide synthesis might have happened in pre-biotic environments.

Hey, going from lightning in a bottle to this is a pretty good step.

This is a key point. RNA is pretty unstable stuff compared to DNA (the extra hydroxyl increases susceptibility to base-catalysed hydrolysis). The mind boggles at how tRNA evolved in the prebiotic soup, never mind how this was coupled with the development of the DNA/RNA triplet code.

Not that RNA in itself isn't amazing stuff. Self-splicing RNA (RNA acting as an enzyme, i.e. ribozymes) is edging into Dr Who territory.

This is quite interesting stuff. The first class I took in grad school was on the origin of life. One of the more perplexing things was what happened inside the ribosome and what facilitated protein synthesis. In particular, the role of aminoacyl tRNA synthetase intrigued me. Many of the other things like the triplet codon and what amino acids they coded for initially were explained either thermodynamically or as a likely chance event. Linking an amino acid to tRNA, however, was a mystery to me because it needs to be both specific and is fundamental to translation. This has rekindled my interest in the topic.

Everyone apparently expected that the sacs would simply grow bigger. Instead, they stretched out into long, thin, branched structures. A bit of gentle agitation, and the strands would fragment back into small sacs, starting the cycle all over again. It was a bit like cell division, but without cells, driven purely by physics and chemistry. "It could have been done many years ago, if we knew what to look for," Szostak said.

Maybe everyone who didn't know much about phase chemistry of surface active materials but that behavior is incredibly well known in surfactant and colloid sciences. The phase behavior of aggregate surfactant materials to form basic micelles and then more advanced structures at higher than CMC concentrations is extremely extremely well known for decades if not more. Shampoos, dishwashing liquids, laundry detergent, even soap to a degree is based off that chemistry.

Ya know - as a casual observer there's something that I've always found well, odd. Life is so prevalent - I mean you can find it practically anywhere here (one is tempted to say Goldilocks zone Shmoldilocks zone) - it just seems like it shouldn't be so hard to get a primitive cell or virus going. I realize a cell is crazy complex, but it just seems like it should be easier.

This is the second time I've heard of this recently. The first time was a really poorly edited video with weak explanations targeted at debunking creationists. That one was unconvincing (and made by different people, who perhaps over-simplified and over-assumed), but this looks pretty solid and rather interesting.

It's also quite different from the hypotheses I've been following most lately: the Alkaline Hydrothermal Vent hypothesis, put forward most clearly by William Martin and Michael J. Russell. In a nutshell: deep sea alkaline vents with microscopically porous semi-permeable Fe/NI-S compartments are supplied with a steady stream of precursor molecules (ammonia, methane, CO, etc.). A temperature, pH, and electrochemical gradient from the surrounding acidic cold ocean provides energy for these to react into more complex molecules. Convection flow through the compartments serves to concentrate them and facilitate further reactions, out of which comes the replicator. Here are some overviews. The first is more general (and a little dated) but a good overall summary. The second is more specific, especially about how nucleic acids may have formed.

Martin, W. & Russell, M.J., 2003. On the origins of cells: a hypothesis for the evolutionary transitions from abiotic geochemistry to chemoautotrophic prokaryotes, and from prokaryotes to nucleated cells. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 358(1429), 59-83; discussion 83-5. Available at: http://rstb.royalsocietypublishing.org/content/358/1429/59.abstract.

I don't have time at the moment to watch through all of the videos (though one suggests formation at a geyser?) or check their publications, so does anyone know if their thoughts are compatible with this? I did grab one of their papers, Expanding Roles for Diverse Physical Phenomena During the Origin of Life (PDF), because it looked like it might be a decent overview of their work, but noticed no references to Martin & Russell's work at all.

One major difference seems to be that they are hypothesizing that membranes came before replicators? Martin & Russell hypothesize that membranes came relatively late after everything else was in place and RNA had given way to DNA for information storage. I don't know which is more plausible, but I've always been impressed with the Martin & Russell hypotheses as they neatly tie up many of the important loose ends such as the concentration problem, the consistency of conditions (constant source of energy and raw materials) problems, and so on, with an interesting hypothesis regarding the differentiation between archaea and eubacteria membrane phospholipids (they hypothesize that the evolutionary divergence between the two domains came before the formation of free living cells).

Anyway, has any read more of Szostak's publications? I'll get around to it, I'm sure, but if anyone has a summary and thoughts about how they compare and contrast with other abiogenesis hypotheses, I'd be very interested in reading them.

DyDx wrote:

There's also a very long ways to go. For example, perhaps other groups are working on it, but Szostak didn't get into how peptide synthesis might have happened in pre-biotic environments.

This is kind of a "holy grail" for molecular evolution as far as I understand it. Assuming you don't mean simply abiotically forming random polypeptides, then the answer to this question is tied up in the question of the origin of the genetic code itself. As far as I know there are few, if any testable hypotheses as of yet regarding it, though last year Wolf and Koonin put forth a rather interesting conceptual framework to try to frame the problem and speculate on what may have happened, opening the door for possible hypotheses and experimentation. Read here:

Wolf, Y.I. & Koonin, E.V., 2007. On the origin of the translation system and the genetic code in the RNA world by means of natural selection, exaptation, and subfunctionalization. Biology direct, 2, 14. Available at: http://www.biology-direct.com/content/2/1/14/.

In a nutshell, it is hypothesized that amino acids may have initially served as cofactors for certain ribozymes (think enzyme but made of RNA instead of protein). Such associations could possibly lead to the first code assignments and the ribozyme or at least parts of it, got "demoted" to tRNA. That is an extreme nutshell. Take a look a the paper, and if it is too in depth, definitely take a look at the diagrams where they sketch out the idea.

Ya know - as a casual observer there's something that I've always found well, odd. Life is so prevalent - I mean you can find it practically anywhere here (one is tempted to say Goldilocks zone Shmoldilocks zone) - it just seems like it shouldn't be so hard to get a primitive cell or virus going. I realize a cell is crazy complex, but it just seems like it should be easier.

Well, it certainly does seem that many organic precursor molecules will form readily enough. The real trick is getting them all together to react and form organized systems. All of the big questions about the origins of life are essentially locked up in how that happened.

When you look at it as chemical reactions happening and re-happening and building up (possibly in a good place for them to get together like they hydrothermal vents hypothesized in my previous post) for a few hundred million years (the projected time from a cool enough and stable enough Earth to the first signs of microbial life in fossils is roughly 300 million years), then yeah in that sense it doesn't seem so "hard". That's a long time and plenty can happen in that time.

This guy spoke at UMass recently. It was very interesting, but I was looking more for a general 'what are the basic conditions and processes needed for life to start' type talk than a 'look at these cool proof-of-principle projects that demonstrate how life might have gotten started.' The only problem I have with the latter is that it's going to be hard if not impossible to prove that these sorts of processes are what actually happened; they could just be one possible way in which it happened.

I don't think it will ever be possible to know, or that anyone is really working on proving what actually happened. The best you can come up with is one or more ways it might have happened. All you need is to find one of the ways -- for the Nobel prize anyways.

The best you can come up with is one or more ways it might have happened.

Is this the way most scientists think?

Regarding the origin of life on Earth? Yes.

It is too complex a process that happened too long ago to get any definitive answer of "this is certainly how it happened". The best answer that may be achieved is "These are experimentally verified plausible steps which would potentially lead to and through abiogenesis and the early evolution of life on Earth." Not all of the steps have been filled in yet, and not all filled in parts have been tested yet.

What organic chemists and molecular biologists who research such things are trying to do is show that that the steps towards going from abiotic geochemistry to biochemistry are physically possible. There may be more than one plausible explanation for the origin of life on Earth, but in trying to understand those possible explanations and show what in what conditions certain aspects of them are experimentally possible, it will give us better insight into how "non-life" might become "life" and what kinds of conditions to look for elsewhere in the universe to try to find life.

Without a time machine, you will not get a definitive answer for the origin of life on Earth. The best you will get is a plausible explanation which fits the evidence. But, then again, that is all science can ever provide about any topic, and many of us are satisfied with that.

When you look at it as chemical reactions happening and re-happening and building up (possibly in a good place for them to get together like they hydrothermal vents hypothesized in my previous post) for a few hundred million years (the projected time from a cool enough and stable enough Earth to the first signs of microbial life in fossils is roughly 300 million years), then yeah in that sense it doesn't seem so "hard". That's a long time and plenty can happen in that time.

I agree, when you're working with geological timescales the transformation of chemistry to biochemistry does not seem so implausible. Does this mean that life has evolved more than once on Earth? Is it happening now, deep down on a black smoker, say? The universal nature of the genetic code (mtDNA oddities excepted), suggests not. This has always puzzled me.

I agree, when you're working with geological timescales the transformation of chemistry to biochemistry does not seem so implausible. Does this mean that life has evolved more than once on Earth? Is it happening now, deep down on a black smoker, say? The universal nature of the genetic code (mtDNA oddities excepted), suggests not. This has always puzzled me.

The simplest explanation is that whichever life formed first most likely won out, so any geochemistry that is tending towards biochemistry quickly has its products exploited by life that's already there. It may not even have needed to be the first one, just the most successful. However, given the near universality of the genetic code, then yes, if there was any such competition, it most probably happened and was decided very early on.

This is something that we'll never know for sure, but we'll probably get more insight about with more experimentation in processes of creating life and especially if we ever manage to completely create artificial life.

Linking an amino acid to tRNA, however, was a mystery to me because it needs to be both specific and is fundamental to translation. This has rekindled my interest in the topic.

Agreed, how RNA knows what proteins to synthesize and when is difficult to grasp and how these systems managed to start and spread in the first place has a chicken and egg feel to it. I guess the most likely solution was precursor processes, simpler instruction sets that relied more on uncoded chemistry to produce effective results. It's like scaffolding going up around a construction site, except the scaffolding itself operated as a functional building until more robust systems replaced it.

Linking an amino acid to tRNA, however, was a mystery to me because it needs to be both specific and is fundamental to translation. This has rekindled my interest in the topic.

Agreed, how RNA knows what proteins to synthesize and when is difficult to grasp and how these systems managed to start and spread in the first place has a chicken and egg feel to it. I guess the most likely solution was precursor processes, simpler instruction sets that relied more on uncoded chemistry to produce effective results. It's like scaffolding going up around a construction site, except the scaffolding itself operated as a functional building until more robust systems replaced it.

The Wolf & Koonin paper I linked above throws out some really interesting ideas about this. Definitely take a look through it. Even if biology isn't your thing, the figures should give you a pretty good idea of what they are talking about.

But, yeah, it is complex, and figuring out a sensible explanation for evolution to make such a thing happen (with no foresight, mind you) is a kind of "holy grail" for molecular evolution.

The best you can come up with is one or more ways it might have happened.

Is this the way most scientists think?

Regarding the origin of life on Earth? Yes.

<Section Removed>

Without a time machine, you will not get a definitive answer for the origin of life on Earth. The best you will get is a plausible explanation which fits the evidence. But, then again, that is all science can ever provide about any topic, and many of us are satisfied with that.

I think that this is one of the killer applications for virtual worlds. Create an early solar system, accelerate time some obscene amount, and check in on it every few (virtual) epochs.

Assuming the environment was programmed somewhat accurately, this could show us things that we might not be expecting.

Hopefully I'll still be alive when we have the computers that could allow such a lab.

Does this mean that life has evolved more than once on Earth? Is it happening now, deep down on a black smoker, say? The universal nature of the genetic code (mtDNA oddities excepted), suggests not. This has always puzzled me.

This is exactly what many scientists are looking for. It makes sense to look for "alien life" right here on earth since we already know it's conducive to life. By "alien" I mean life that arose independently of that which currently dominates the biosphere and operates on different principles than our known life. One of the major issues is knowing what you've found when you've found it.

Does this mean that life has evolved more than once on Earth? Is it happening now, deep down on a black smoker, say? The universal nature of the genetic code (mtDNA oddities excepted), suggests not. This has always puzzled me.

This is exactly what many scientists are looking for. It makes sense to look for "alien life" right here on earth since we already know it's conducive to life. By "alien" I mean life that arose independently of that which currently dominates the biosphere and operates on different principles than our known life. One of the major issues is knowing what you've found when you've found it.

IANAS however I think one of the problems with life evolving right now is that the proteins, and other building blocks needed to for life to evolve will be eaten by life that is already here long before they can arrange themselves into a new form of life.

Not that it couldn't happen, but I think you'd need to look for life that uses an energy source, or is based on a chemical make up that is different enough from current life, that current life would have no interest in it.